Clinical review

Hereditary ovarian carcinoma

Lidia Kasprzak, genetic counsellor, ^a William D Foulkes, assistant professor, ^a Andrew N Shelling, lecturer in reproductive science. ^b

^a Division of Medical Genetics, Department of Medicine, McGill University, Montreal, Quebec, Canada H3G 1A4, ^b Research Centre in Reproductive Medicine, Department of Obstetrics and Gynaecology, National Women's Hospital, Auckland, New Zealand

Correspondence to: Dr W D Foulkes, Department of Medicine, L10-116, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec, Canada H3G 1A4 mdwf{at}musica.mcgill.ca

Ovarian carcinoma is the fourth most common cause of cancer death in women in Western countries. Because of inadequate screening methods and the vague nature of the symptoms, patients present late in the course of the disease and the survival rate is poor. There are no strong environmental risk factors, and after age is controlled for the most important risk factor is a family history of ovarian carcinoma. The effect of a positive family history on a woman's risk of ovarian carcinoma is illustrated in table 1. In this review we focus on the hereditary aspects of ovarian carcinoma.

	Methods

Top Methods Hereditary fraction of ovarian... BRCA1, BRCA2, and mismatch... Hereditary ovarian carcinoma... Histology of hereditary and... Feasibility of early diagnosis... Differences in prognosis Conclusions References

We reviewed original articles and expert reviews from journals cited in Medline between 1980 and 1998 and supplemented this information with unpublished data from our colleagues. We also included information from recently published books. In performing the Medline searches we used the following key words: hereditary ovarian carcinoma, breast and ovarian carcinoma syndrome, ovarian cancer screening, prophylactic oophorectomy.

	Hereditary fraction of ovarian carcinoma

Top Methods Hereditary fraction of ovarian... BRCA1, BRCA2, and mismatch... Hereditary ovarian carcinoma... Histology of hereditary and... Feasibility of early diagnosis... Differences in prognosis Conclusions References

Between 5% and 10% of cases of ovarian carcinoma are the result of an inherited gene or genes. The percentage depends on the degree of relatives included in the calculation and the method of case ascertainment.² Narod et al interviewed 450 unselected women with ovarian carcinoma in Ontario, Canada and found that hereditary forms accounted for at least 4% and possibly as much as 8% of cases.³ Some groups give higher figures (table 1).⁴

The inherited fraction of ovarian carcinoma may differ between populations. One of highest rates of ovarian carcinoma in the world is seen in Israeli Jews born in North America or Europe (age standardised incidence rate, 13.5 per 100 000).⁵ Most of these women will be of Ashkenazi Jewish descent, and in this population the prevalence of disease associated alleles of BRCA1 and BRCA2 is extremely high ( about 1 in 50). By contrast, probably 1 in 800 non-Jewish women carry a mutated allele of BRCA1.⁶

Although the most common hereditary form of ovarian carcinoma occurs in women with BRCA1 or BRCA2 mutations, ovarian carcinoma is one of the many extracolonic tumours which arise in families with hereditary non-polyposis colorectal cancer. The two most frequently mutated genes in hereditary non-polyposis colorectal cancer are hMSH2 and hMLH1, and the risk of ovarian carcinoma seems to be raised in carriers of mutations in either of these genes. The cumulative lifetime risk of ovarian carcinoma could be as high as 9%.⁷ Large studies will be required to define precisely ovarian carcinoma risks in carriers of different gene mutations associated with hereditary non-polyposis colorectal cancer.

Data from early genetic linkage studies, in which only large families with several affected members were included, indicated that if a mutated allele of BRCA1 were inherited by a woman, she had a 87% chance of developing breast cancer and a 44% chance of developing ovarian cancer up to age 70.⁸ Subsequent population based studies have indicated that the risks may be lower than this50%-80% for breast cancer and 20%-50% for ovarian cancer. Whether the differences are real or a result of methodological factors is uncertain. The population risks of breast and ovarian cancer for North American women are currently 7.5% and 1.4% respectively.

In the recent study of breast cancer families collected by the Breast Cancer Linkage Consortium, the estimated cumulative risks of ovarian carcinoma in families carrying a BRCA2 mutation were 0.4% (95% confidence interval 0% to 1%) by the age of 50 and 27% (0% to 47%) by the age of 70.⁹ Although recent data suggest that an ovarian carcinoma cluster region in exon 11 of the BRCA2 gene confers a higher risk of ovarian carcinoma,¹⁰ not all studies support this finding. ^{11 12}

	BRCA1, BRCA2, and mismatch repair genes

Top Methods Hereditary fraction of ovarian... BRCA1, BRCA2, and mismatch... Hereditary ovarian carcinoma... Histology of hereditary and... Feasibility of early diagnosis... Differences in prognosis Conclusions References

The genes implicated in hereditary ovarian cancer are given in table 2. Most hereditary ovarian carcinoma is associated with germline mutations in BRCA1 or BRCA2. On the basis of a gene frequency of 0.0006, the estimated proportion of ovarian carcinoma in the general population resulting from mutations in these two genes would be 5.7% in women aged less than 40, 4.6% in women aged 40-49, and 2.1% in those aged 50-70.⁶ BRCA1 is nearly always implicated in breast-ovarian cancer families with two or more cases of early onset breast cancer and two or more cases of ovarian carcinoma.¹³

Mutations in BRCA2 probably account for fewer than 10% of cases of hereditary breast-ovarian carcinoma. Nearly all site specific hereditary ovarian carcinoma (figure) is a result of BRCA1 or BRCA2 mutations,^14-17 and is rarely, if ever, attributable to mutations in mismatch repair genes (responsible for hereditary non-polyposis colorectal cancer). In addition, germline mutations in p53 seem to be very uncommon in women with ovarian carcinoma and have been reported only rarely in families with ovarian or breast-ovarian carcinoma.^18-20

View larger version (22K): [in this window] [in a new window]   Pedigree of family with site specific ovarian cancer. Black symbols indicate affected members; numbers in parentheses give age at diagnosis. A BRCA1 mutation was identified in several affected people

	Hereditary ovarian carcinoma and age of onset

Top Methods Hereditary fraction of ovarian... BRCA1, BRCA2, and mismatch... Hereditary ovarian carcinoma... Histology of hereditary and... Feasibility of early diagnosis... Differences in prognosis Conclusions References

One of the key observations in cancer family syndromes is that the cancer presents at an early age. Most, but not all, ^{4 21} studies have stated that hereditary forms of ovarian carcinoma occur at an earlier age than does sporadic disease.^22-24 The apparent excess of early onset disease in some family studies may reflect biases in ascertainment resulting from preferential referral of young women with ovarian carcinoma to registries of familial cancer.²⁵ Data from the Ontario Cancer Registry (S Narod, personal communication) indicate that the age of onset of ovarian cancer is almost 10 years earlier in carriers of the BRCA1 mutation than in carriers of the BRCA2 mutation (50.2 years v 59.9 years); in sporadic cases the mean age was 56.2 years. Thus, the lack of any effect of age that is seen in some studies of hereditary disease could be related to the later age of disease onset in women carrying the BRCA2 mutation masking the earlier age of onset in women carrying the BRCA1 mutation.

	Histology of hereditary and sporadic disease

Top Methods Hereditary fraction of ovarian... BRCA1, BRCA2, and mismatch... Hereditary ovarian carcinoma... Histology of hereditary and... Feasibility of early diagnosis... Differences in prognosis Conclusions References

In a comprehensive study of the Gilda Radner Familial Ovarian Cancer Registry, noticeable differences in the distribution of histological types of ovarian carcinoma were observed in familial and sporadic ovarian cancer.²³ The most important difference was that mucinous adenocarcinomas are rarely seen in familial cancer (1.4% v 12.7% in sporadic disease). In a hospital based series, 83% of patients with familial ovarian carcinoma and only 49% of matched controls had a serous cystadenocarcinoma.²⁶ These findings were confirmed in patients with ovarian carcinoma associated with a BRCA1 mutation, in whom 34 of 36 tumours were of serous histology (S Narod, personal communication).

In several studies, fewer borderline tumors have been noted in familial ovarian carcinoma than in sporadic disease. ^{2 23} In a study of the prevalence of the BRCA1 mutation in 374 women with ovarian carcinoma, 12 of 13 patients with BRCA1 mutations had serous cystadenocarcinomas, and the remaining woman had a borderline mucinous cystadenocarcinoma.²⁷

	Feasibility of early diagnosis or prevention

Top Methods Hereditary fraction of ovarian... BRCA1, BRCA2, and mismatch... Hereditary ovarian carcinoma... Histology of hereditary and... Feasibility of early diagnosis... Differences in prognosis Conclusions References

Detection
Detecting ovarian carcinoma at a stage when it might be curable surgically or more amenable to chemotherapy would improve the prognosis appreciably. The traditional screening methods for ovarian carcinoma are measurement of the serum tumour marker CA 125, transvaginal ultrasonography, and clinical examination. None of these methods alone achieves the required level of sensitivity. For example, CA 125 measurement detects only about 50% of stage 1 ovarian tumours.²⁸ In the general population, clinical examination, transabdominal²⁹ and transvaginal ^{30 31} ultrasonography, and serum CA 125 screening tests,³² either alone or in combination,³³ have been assessed as potential screening tests in various settings. However, no test or combination of tests has yet proved to be practical for population screening. It is recommended that women at high risk of ovarian carcinoma have an annual pelvic examination and vaginal ultrasonography, and serum CA 125 measurement every 6 or 12 months from their mid 20s or when they are 5 years younger than the youngest affected member of the family, whichever is sooner.³⁴ Screening trials in high risk women and in the general population are under way in the United States and in Europe.

Prevention

Hormonal factors
Use of the contraceptive pill can reduce substantially the risk of ovarian carcinoma in the general population.³⁵ One study showed that women with a family history of ovarian carcinoma would benefit from using oral contraceptives for a lengthy period of time.³⁶ Godard et al found that late use of the contraceptive pill (at 35-43 years of age) had a protective effect against familial ovarian carcinoma,³⁷ and Narod et al extended these observations to proved carriers of the BRCA1 mutation.³⁸

Surgical measures
Only women with a proved family history of hereditary ovarian carcinoma should be offered a prophylactic oophorectomy.⁴⁰ Peritoneal carcinomatosis has developed in some women after prophylactic oophorectomy. Three of 28 (11%) women with a family history of breast and ovarian cancer who underwent prophylactic oophorectomy subsequently developed intra-abdominal carcinomatosis that was indistinguishable from ovarian carcinoma.⁴¹ This suggests that the carcinoma develops from the peritoneum itself, which shares a common embryological origin with the ovarian epithelium and can undergo malignant transformation either simultaneously with the ovary or as the primary carcinoma.

	Differences in prognosis

Top Methods Hereditary fraction of ovarian... BRCA1, BRCA2, and mismatch... Hereditary ovarian carcinoma... Histology of hereditary and... Feasibility of early diagnosis... Differences in prognosis Conclusions References

A study to determine the clinicopathological features of hereditary ovarian carcinoma associated with BRCA1 enrolled 53 ovarian carcinoma patients with germline BRCA1 mutations: 43 (81%) had serous adenocarcinomas and 38 (72%) were stage 3 at presentation.⁴³ The actuarial median survival for the 43 women was 77 months, compared with 29 months for the control group matched for age, tumour stage, and histological type, who were believed not to have mutations in BRCA1 on the basis of family history (P<0.001, log rank test). This surprisingly good prognosis was attributed partly to the youth of the patients (mean age 48 years). It was also thought to be related directly to the presence of a BRCA1 mutation. A better prognosis was also observed in a Japanese study.⁴⁴

Other studies have shown that the survival is similar for hereditary and sporadic ovarian carcinoma. ^{45 46} In a Canadian study of 44 women with ovarian cancer from families with the BRCA1 mutation,⁴⁵ the actuarial median survival was 2.6 years and the five year survival was 32.6%values similar to those observed in the control groups of two other studies. ^{43 46} Therefore, on current evidence it seems that the prognosis for hereditary ovarian carcinoma does not differ from that for sporadic ovarian cancer, and we counsel our patients accordingly.

	Conclusions

Top Methods Hereditary fraction of ovarian... BRCA1, BRCA2, and mismatch... Hereditary ovarian carcinoma... Histology of hereditary and... Feasibility of early diagnosis... Differences in prognosis Conclusions References

Hereditary ovarian carcinoma is uncommon: it accounts for at most 5%-10% of all cases of ovarian carcinoma. However, in some ethnic groups such as Ashkenazi Jews this figure is much higher (about 30%). When assessing the likelihood of a hereditary cause for ovarian carcinoma, the three most important questions to answer are:

• Is there a family history of breast, ovarian, or colorectal carcinoma?
• What is the histological type of the ovarian carcinoma?
• What is the ethnic origin of the patient?

Ovarian carcinoma is difficult to detect early. Use of the contraceptive pill lowers the risk of ovarian carcinoma, and hormonal treatment may offer the best hope for prevention of the disease. Prophylactic oophorectomy may benefit women at highest risk, but the efficacy of this procedure is unknown. Early detection, prevention, and treatment of hereditary ovarian carcinoma are among the most challenging aspects of cancer genetics. With the current pace of research, new information is likely to be available over the next few years.

	Acknowledgments

We thank Dr Steven Narod for sharing unpublished data with us. We apologise to the many investigators who could not be cited in our review because of the constraints of space.

	References

Top Methods Hereditary fraction of ovarian... BRCA1, BRCA2, and mismatch... Hereditary ovarian carcinoma... Histology of hereditary and... Feasibility of early diagnosis... Differences in prognosis Conclusions References

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(Accepted 15 December 1998)